Diabetes mellitus is a disease of major global importance, increasing in frequency at almost epidemic rates, such that the worldwide prevalence in 2006 is 170 million people and predicted to at least double over the next 10-15 years. Diabetes is characterized by a chronically raised blood glucose concentration (hyperglycemia), due to a relative or absolute lack of the pancreatic hormone, insulin. Within the healthy pancreas, beta cells, located in the islets of Langerhans, continuously produce and, secrete insulin according to the blood glucose levels, maintaining near constant glucose levels in the body.
Much of the burden of the disease to the user and to health care resources is due to the long-term tissue complications, which affect both small blood vessels (microangiopathy, causing eye, kidney and nerve damage) and large blood vessels (causing accelerated atherosclerosis, with increased rates of coronary heart disease, peripheral vascular disease and stroke). The Diabetes Control and Complications Trial (DCCT) demonstrated that development and progression of the chronic complications of diabetes are greatly related to the degree of altered glycemia as quantified by determinations of glycohemoglobin (HbA1c). [DCCT Trial, N Engl J Med 1993; 329: 977-986, UKPDS Trial, Lancet 1998; 352: 837-853. BMJ 1998; 317, (7160): 703-13 and the EDIC Trial, N Engl J Med 2005; 353, (25): 2643-53]. Thus, maintaining normoglycemia by frequent glucose measurements and adjustment of insulin delivery accordingly can be of utmost importance.
Insulin pumps have been available which deliver rapid acting insulin (e.g. Lispro, Aspart, etc.) 24 hours a day through a catheter placed under the skin. Rapid acting insulin effect begins in about 10 minutes, peaks at one to one and a half hours and ends in about two to six hours after the administration. The interval between insulin injection and end of its activity is defined as Duration of Insulin Activity (DIA) or Residual/Remaining Insulin time (RI time).
A simple rule can be applied to calculate the duration of insulin activity, i.e., the DIA. It is often stated that each hour after bolus dose administration, 20% of the dose becomes effective, so that after 5 hours there is no active insulin remaining in the body. FIG. 1 shows the insulin consumption according to the described rule (adapted from Using Insulin© 2003). One of the major advantages of using insulin pumps is the convenience of insulin bolus administration at any desired time. However, boluses may overlap and it can be useful to know the amount of active insulin that is still “working”/effective in the body, i.e. the RI. Accumulation of insulin may lead to life-threatening hypoglycemia. This is especially important at bedtime since users are usually unaware of nocturnal hypoglycemia.
Conventional insulin pumps can apply the abovementioned rule to calculate the residual insulin and subtract the calculated value from administered bolus. For example, based on FIG. 1, if a desired 5 U bolus is administered 2 hours after a 6 U bolus, the RI=3.6 U and the actually delivered bolus should be 1.4 U (5 U-3.6 U). If however an additional bolus of 5 U was delivered 4 hours before the desired 5 U bolus administration, the total RI is 3.6 (6 U minus 40% of 6 U) plus 1 U (5 U minus 80% of 5 U). The total RI (i.e. 3.6 U+1 U=4.6 U) is then subtracted from the desired 5 U bolus to yield a bolus dose of merely 0.4 U (5 U-4.6 U).
Bolus recommendations provided by portable insulin pumps that include bolus calculators (and other types of bolus determining units) take into consideration the residual insulin. For example, in U.S. Pat. No. 6,936,029 assigned to Medtronic Minimed, a pump provided with a bolus calculator and an algorithm for calculating the amount of insulin to be administered is described. The algorithm is based on a formula for calculating a bolus, depending on the user's insulin sensitivity (IS), carbohydrate-to-insulin ration (CIR), target blood glucose (TBG), RI, BG and carbs intake inputted by the user.
The recommended bolus is calculated as:
      Recommended    ⁢                  ⁢    bolus    =                    (                  TC          /          CIR                )                    ︸                                                           ``                        ⁢            Food                    ⁢                                          ⁢                      estimate            ″                                +                                        (                          CBG              -              TBG                        )                    /                          ︸                                                                     ``                            ⁢              Correction                        ⁢                                                  ⁢                          estimate              ″                                          ⁢      IS        -    RI  where TC—total amount of carbohydrates; CIR—carbohydrate-to-insulin ratio; TBG—target blood sugar; CBG—current blood sugar; IS—insulin sensitivity; and RI—residual insulin.
The residual insulin is also considered in the bolus recommendation feature described in co-owned/co-pending U.S. publication no. US2008/0234663 and international patent application no. PCT/IL2009/000454, the disclosures of which are incorporated herein by reference in their entireties. This bolus recommendation feature comprises sets of grids/tables of ranges of carbohydrate and blood glucose level. Each grid corresponds to a different combination of IS, CIR, and TBG. Additional grids correspond to selected bolus doses and residual insulin values. The final recommended dose is related to a value that is substantially equivalent to the selected bolus dose minus the RI.
Application of the abovementioned rule (as shown in FIG. 1) can lead to over- or under-dosing of insulin due to significant individuality variability of insulin absorption and consumption which varies among different patients. The assumption that the complete bolus absorption time (a state in which there is no residual insulin, RI=0) is always 5 hours (i.e. assuming 20%/hour), ignores the individual variability, and, as a result, may not be correct. A more accurate, user specific assessment of the RI time is described in co-owned, co-pending international publication no. WO2009/060433, the disclosure of which is hereby incorporated by reference in its entirety. Generally, the described procedure for assessing residual insulin (RI) time of a patient comprises: allowing the patient to fast during a period of time, determining a known amount of carbohydrates to be administered to the patient, based on the determined amount of carbohydrates, administering an insulin bolus to the patient, administering the determined amount of carbohydrates to the patient, subsequently periodically measuring blood glucose (BG) levels of the patient at predetermined times for indication of at least two successive substantially equal values, or values within a predetermined range, and calculating the RI time based on the time span between the insulin administration to the first measurement of the at least two successive equal values.
Furthermore, it has been shown that the remaining insulin time is volume dependent. For example, at a certain concentration (e.g., 100 U/ml), a smaller insulin volume (e.g., 2 U) is absorbed faster than a larger volume (e.g., 20 U) (Journal of Diabetes Science and Technology, 2007 Vol. 1 (5), pp. 780-793). FIG. 2 shows an example of a graph of the percentage of insulin remaining at the injection site versus elapsed time after subcutaneous injection. It can be seen that the lower the subcutaneously injected volume, the steeper is the decline of the percentage of insulin remaining at the injection site as a function of time after the injection. In other words, it can be seen that the RI time is a function of the injected dose—the lower the dose, the shorter the RI time.